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Fallout 3 had previously started work on two occasions prior to the development of Van Buren, both attempts were halted by Titus Software in favor for other of Interplay's titles, notably console titles. When Interplay lost the rights to make Icewind Dale and Baldur's Gate video games for the PC, their game Baldur's Gate III: The Black Hound, in development by Black Isle Studios, was canceled. With the cancellation of Baldur's Gate III, Black Isle Studio's team was immediately transferred to work on Fallout 3, codenamed Van Buren. During this time, Interplay's own team was working on Fallout: Brotherhood of Steel, the teams had one meeting together to plan out the games. When many of Black Isle Studio's most talented developers left Black Isle Studios, the developer Damien Foletto responded by stating it was only the trust within the team and belief that they could finish the game that kept them going. The game was officially canceled when Titus decided to try and improve Interplay's console division. This led to a nearly completed Fallout 3 being canceled. Members of the Black Isle team were then either transferred to the development of Fallout: Brotherhood of Steel 2 or Baldur's Gate: Dark Alliance II, of which only the latter was released.[2]

Although the complete story of Van Buren was never revealed, many important details were divulged prior to its cancellation.

The player's character would start the game as a prisoner; whether the character was wrongfully imprisoned or guilty was to be determined at character creation. The game would have started in a strange prison as it was attacked by an unnamed force. An explosion would knock the character unconscious, and the cell door would be open when he awakened. The player would then escape into the wasteland while being pursued by strange assailants. After leaving, the character would have the power to shape the destiny of the wasteland. His interactions with organizations such as the Brotherhood of Steel and the burgeoning New Californian Republic (with both of these factions participating in a prolonged war with one another) could bolster or destroy the organizations, influencing people associated with them and eventually decide the fate of the region, much as in the previous two Fallout games.

One of the more significant elements of the plot and back story of Van Buren was to be an ongoing war between the Brotherhood of Steel and the New California Republic. The player would be able to visit various prominent settlements and fortresses controlled by either of the factions and their actions there would influence the proceeding of the war. An example of the how the player's interactions could alter the flow of the conflict would be in the case of the settlement situated in the area around the Hoover Dam. Here the player could choose whether or not to aid the settlement and its people in a myriad of tasks, which would lead to this isolated frontier outpost eventually deciding the fate of the war. The game's ultimate plot line was planned so that the events in the beginning of the game would have been part of a scheme by a rogue New California Republic scientist, Dr. Victor Presper, to seize control of a U.S. orbital nuclear weapons platform dubbed B.O.M.B.-001 and use it to initiate a second nuclear holocaust, cleansing the world of all but his chosen few. In the end, the player would not be able to stop all of the missiles from launching, and his or her decisions on where the missiles would strike would ultimately have decided the future of the world.

The official Fallout 3 does not follow the storyline of the cancelled project, but during an interview, Avellone revealed that aspects from Van Buren would make an appearance in Fallout: New Vegas. In particular, the NCR-Brotherhood of Steel war is mentioned, a companion from Van Buren (Joshua Graham) appears in heavily modified form, as does an antagonistic faction known as Caesar's Legion. He also verified that the Van Buren codename was based on President Martin Van Buren.[3] Of the locales planned to be in Van Buren, only Hoover Dam appeared in Fallout: New Vegas, due to the change in location.